Aging theories: Is there a unifying factor in aging?

When Darwin’s theory of evolution by natural selection was established, biologists were puzzled by the existence of senescence and aging among all organisms. Why did the evolutionary pressure not produce immortal species? They concluded that even the power of evolution has its limitations. It took almost hundred years to reach the idea that mortal individuals may be preferred by nature for following reasons — the genes resulting in advantage in early life might cause damage in late life, and the reproduction starts as soon as possible. Around the middle of twentieth century, there finally was a framework for the gerontological research conduced in the following decades — the first evolutionary theories of aging (Gavrilov & Gavrilova, 2002).
There are two major groups of theories aiming to explain the mechanism of aging, so-called programmed and error theories. The programmed ones are based on the senescence-causing nature of certain genes (these are also called evolutionary theories), hormones or the immune system. Error theories claim that we age because of general damage caused by cell weariness, metabolic rate, cross-linked proteins, free radicals or somatic DNA changes (Jin, 2010).
The beauty of various aging theories is that most of them are not mutually exclusive. We can see that newer theories do not necessarily oppose the old ones, but rather shed more light and offer more in-depth views on the process of senescence.
The pioneering idea from 1882 was Weismanns’s theory of programmed death (also called wear-and-tear theory) claiming something like apoptosis of the multicellular organism. Although disproved by experiments, his theoretical explanation of the mechanism predicted the discovery of Hayflick limit (Gavrilov & Gavrilova, 2002). According to Weismann’s first conception, nature priorities young individuals over elderly because of limited resources.
Pearl stated his ‘rate of living’ theory of aging in 1928, although the idea comes from Rubner who, in 1908, suggested that every organism has limited amount of metabolic energy and therefore its age depends on the rate of metabolism which correlates with organism’s size (Pearl, 1928). Most consider the rate of living theory to be flawed (Lints, 1989; de Magalhaes, Costa, & Church, 2007; Vaanholt, Daan, Schubert, & Visser, 2009).
A few decades later, the following evolutionary models have emerged:
Medawar’s hypothesis of mutation accumulation proposes that aging is a by-product of natural selection — genes causing senescence in later stadium of life cannot be eliminated because the genetic information was most likely already transferred to successors by individuals in their early adulthood (Gavrilov & Gavrilova, 2002). This theory from 1952 is considered the first modern theory of aging. Charlesworth confronted Medawar’s model with a discovery of late-life mortality plateaus and in 1994 presented so-called modified mutation accumulation theory (Charlesworth, 2001; Ljubuncic & Reznick, 2009).
In his antagonistic pleiotropy theory (also called ‘pay later’ theory), Williams in 1957 expressed the idea that even the same genes which cause trouble at advanced age may be advantageous in earlier stages of life, and therefore be not only tolerated, but even preferred by natural selection (Gavrilov & Gavrilova, 2002).
In 1979, Kirkwood extended this theory to the disposable soma theory — organisms may save energy by reducing accuracy in cells metabolism and invest it in faster development and reproduction (Kirkwood & Holliday, 1979). This is the last one of famous, genes-orientated evolutionary models.
The following can be classified as programmed theories:
The neuroendocrine theory proposed in 1954 by Dilman says that the main cause of aging is a loss of receptor sensitivity of the hypothalamus over time, and therefore its control of adequate production of hormones declines which leads to ineffectiveness and lower hormone levels in organism. It is an attempt to explain a high occurrence of degenerative diseases in late age (“Neuroendocrine Theory of Aging: Chapter 1,” 1999). Research on hormonal signaling pathways confirms that hormone levels have at least a partial role in determining longevity (van Heemst et al., 2005).
In 1964, Walford suggested his immunologic theory of aging — due to increasing diversity of cells, the immune system looses its efficiency with age which leads to insufficient responses against pathogens as well as to autoimmune reactions against self proteins (Walford, 1964).
All following attempts to explain the mechanism behind a process of aging are usually called error or damage theories.
Bjorksten’s "crosslinkage theory" says that proteins become linked together in presence of certain crosslinking agents, and after some time, accumulation of these molecular aggregates causes decline in tissue functions. This theory from 1942 is no longer popular (Bjorksten, 1968). Later research has showed that advanced glycation end products (AGEs) accumulate in collagen and lead to outcomes predicted by Bjorksten (Verzijl et al., 2002; Aronson, 2003).
These days very popular among researchers and public, the free radical theory was suggested by Harman in 1956. His idea was that the occurrence of free radicals, or reactive oxygen species naturally produced in living organisms, leads to macromolecular damage which accumulates and causes physiological changes known as senescence (Harman, 2009). Later he suggested the reactive oxygen species formation takes place mainly in mitochondria which causes a decline in important mitochondrial functions (Harman, 1972). Because of the theory’s popularity, various extensions of Harman’s model were created, usually considering different sites as a main target of free radicals.
Failla’s somatic mutation theory from 1958 posits that increasing number of mutations of genetic material causes a decrease in cellular, organ and body functions (Failla, 1958; Gensler & Bernstein, 1981; Kennedy, Loeb, & Herr, 2012). The theory received a lot of criticism in previous decades (Vijg, 2000). Kaya, Lobanov and Gladyshev (2015) investigated aging in yeast and failed to find evidence in support of Failla’s thesis.
Orgel proposed his error catastrophe theory in 1963. He saw the cause of aging in accumulation of malfunctioning proteins coming from errors during protein translation (Orgel, 1963). This theory never gained popularity and was soon disproved (Gershon & Gershon, 1976).
Alexander in 1967 extended Failla’s theory by hypothesizing that DNA damage instead of mutation is the cause of aging (Alexander, 1967). These days, this version called
"somatic DNA damage theory of aging" is more often used by scientists (Freitas & de Magalhaes, 2011; Soares et al., 2014). Evidence suggests that more damage happens in mitochondrial DNA than in nuclear DNA (Ames, 2009).
In 2002, Brunk and Terman published the mitochondrial-lysosomal axis theory. It states that defective macromolecules derived from mitochondria undergo further changes in lysosomes to become lipofuscin inclusions. These end products decrease cell’s autophagocytotic capacity which leads to more mitochondrial defects (Brunk & Terman, 2002).
Zs.-Nagy’s "membrane hypothesis" focuses on a decline of mitochondrial functions due to lessened membrane permeability caused by residual heat coming from nerve signals as well as by reactive oxygen species (Zs.-Nagy, 2014).
Recent versions of damage theories claim that free radicals are only one kind of senescence-causing by products of metabolism but the real initiator of all the inevitable damage is biological imperfectness. In other words, there are always types of damage which lack adequate repair mechanisms in organism and the most severe source of errors depends on actual conditions (Gladyshev, 2013; Gladyshev, 2014). This idea comes from the
"reliability theory", which focuses on systems failure in machines (Gavrilov & Gavrilova, 2001).
In spite of many research programs and lots of scientists involved, the unifying factor in aging is at the moment still unknown.

References

Alexander, P. (1967). The role of DNA lesions in the processes leading to ageing in mice. Symp Soc Exp Biol, 21, 29-50.

Orgel, L. (1963). The Maintenance of the Accuracy of Protein Synthesis and its Relevance to Ageing. Proceedings Of The National Academy Of Sciences, 49(4), 517-521.
http://dx.doi.org/10.1073/pnas.49.4.517